Synthesis of 1,3-Dihydro-2,1-benzisoxazoles by Intramolecular C–N Coupling: Evaluation as an Indane Bioisostere

Abstract

Despite the ever-increasing interest in isoxazole-based compounds, benzo-fused isoxazolidines, or 1,3-dihydro-2,1-benzisoxazoles, are very rare. Seeking to fill this gap, we present a method for the synthesis of 1,3-dihydro-2,1-benzisoxazoles by intramolecular Cu-mediated or Pd-catalyzed C–N coupling of bromoaryl benzylic hydroxylamine derivatives, which can be further derivatized through a simple reductive amination sequence. This approach overcomes the limitations of previous methods and provides access to multiple novel heterocyclic scaffolds. As a proof of concept, we apply the method to the synthesis of a benzisoxazoline analogue of the metabolically labile chiral indane-based MT1/MT2 receptor agonist ramelteon, ultimately furnishing a compound with a >10-fold improvement in metabolic stability in human hepatocytes. Support for the bioisosteric nature of the 1,3-dihydro-2,1-benzisoxazole and indane cores was provided in the context of the ramelteon analogue by DFT calculations.